Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM‐associated syndromes

Abstract

The MECOM gene encodes multiple protein isoforms that are essential for hematopoietic stem cell self‐renewal and maintenance. Germline MECOM variants have been associated with congenital thrombocytopenia, radioulnar synostosis and bone marrow failure; however, the phenotypic spectrum of MECOM‐associated syndromes continues to expand and novel pathogenic variants continue to be identified. We describe eight unrelated patients who add to the previously known phenotypes and genetic defects of MECOM‐associated syndromes. As each subject presented with unique MECOM variants, the series failed to demonstrate clear genotype‐to‐phenotype correlation but may suggest a role for additional modifiers that affect gene expression and subsequent phenotype. Recognition of the expanded hematologic and non‐hematologic clinical features allows for rapid molecular diagnosis, early identification of life‐threatening complications, and improved genetic counseling for families. A centralized international publicly accessible database to share annotated MECOM variants would advance their clinical interpretation and provide a foundation to perform functional MECOM studies.

Perinatal-lethal nonimmune fetal hydrops attributed toMECOM-associated bone marrow failure

“…In both cases, genomic sequencing (ES or GS) revealed variants in MECOM to which these severe and lethal presentations were attributed. Disease-causing variants in MECOM are associated with a bone marrow failure syndrome typically characterized by early-onset thrombocytopenia that progresses into pancytopenia and is accompanied by radioulnar synostosis, though variable expressivity is well-described ( Niihori et al 2015 ; Lozano Chinga et al 2023 ). Although mildly affected individuals with pathogenic variants in MECOM have been reported, including those with the radial findings only and no bone marrow failure ( Germeshausen et al 2018 ), our cases highlight the lethal nature of this disorder as well as its possible manifestation as fetal hydrops.…”

“…EVI1 is believed to play an essential part in hemopoietic stem cell activity, as supported by murine experiments ( Yuasa et al 2005 ). Mecom expression has also been identified in high levels to the urinary system, lungs, heart, and limb buds of mice embryos ( Perkins et al 1991 ), suggesting that pathogenic variants in this gene may lead to multiorgan anomalies ( Lozano Chinga et al 2023 ). Variants in MECOM leading to a bone marrow failure syndrome were first identified in three individuals with radioulnar synostosis and thrombocytopenia, two of whom presented at birth with severe anemia, similar to our cases ( Niihori et al 2015 ).…”

“…Bone marrow failure syndromes are rare conditions that, when responsible for congenital anemia, may manifest as nonimmune fetal hydrops ( Adam et al 2017 ; Quinn et al 2021 ). A specific combination of bone marrow failure and bilateral radioulnar synostosis, RUSAT2 (radioulnar synostosis with amegakaryocytic thrombocytopenia 2, MIM #616378), has been linked to damaging variants in MECOM , comprised of complex loci MDS1 (myelodysplastic syndrome 1) and EV11 (ecotropic viral integration site 1) ( Niihori et al 2015 ; Bluteau et al 2018 ; Germeshausen et al 2018 ; Lord et al 2018 ; Loganathan et al 2019 ; Lozano Chinga et al 2023 ). MECOM encodes multiple protein isoforms through the alternative splicing of these loci, is expressed in hematopoietic stem cells (HSCs), and plays a role in regulating HSC self-renewal ( Bard-Chapeau et al 2012 ; Kataoka and Kurokawa 2012 ).…”

“…Although the RUSAT phenotype was first associated with variants in HOXA11 ( Thompson and Nguyen 2000 ), subsequent genomic analyzes of individuals with RUSAT without evidence of aberration in HOXA11 identified damaging variants in MECOM , leading to the delineation of RUSAT2 as a distinct condition ( Niihori et al 2015 ). Variations in the classical presentation of RUSAT2 have been reported, with certain individuals harboring damaging MECOM variants manifesting with bone marrow failure without radioulnar synostosis; other features such as hand abnormalities, heart defects, renal malformations, and sensorineural deafness have also been reported ( Germeshausen et al 2018 ; Lozano Chinga et al 2023 ). Thus, disease-causing variants in MECOM , which are transmitted in an autosomal dominant pattern, are associated with a phenotypic spectrum encompassing RUSAT2 in addition to variable degrees of bone marrow failure without radioulnar synostosis ( Lozano Chinga et al 2023 ).…”

“…Variations in the classical presentation of RUSAT2 have been reported, with certain individuals harboring damaging MECOM variants manifesting with bone marrow failure without radioulnar synostosis; other features such as hand abnormalities, heart defects, renal malformations, and sensorineural deafness have also been reported ( Germeshausen et al 2018 ; Lozano Chinga et al 2023 ). Thus, disease-causing variants in MECOM , which are transmitted in an autosomal dominant pattern, are associated with a phenotypic spectrum encompassing RUSAT2 in addition to variable degrees of bone marrow failure without radioulnar synostosis ( Lozano Chinga et al 2023 ).…”